Indications for Anti-IL-1 Beta Therapy

ABSTRACT

This invention relates to a novel use of IL-1β-ligand/IL-1 receptor disrupting compounds (herein referred to as “IL-1beta Compounds”); such as small molecular compounds disrupting IL-1β ligand-IL-1 receptor interaction, IL-1β antibodies or IL-1 receptor antibodies, e.g. IL-1β binding molecules described herein, e.g. antibodies disclosed herein, e.g. IL-1β binding compounds or IL-1 receptor binding compounds, and/or RNA compounds decreasing either IL-1β ligands or IL-1 receptor protein levels, in the treatment and/or prevention of auto-inflammatory syndromes, e.g. Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and to methods of treating and/or preventing auto-inflammatory syndromes, e.g. Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome, in mammals, particularly humans.

This is a National Stage of International Application No.PCT/EP08/056,520 filed on May 28, 2008, which claims benefit of EuropeanApplication No. 07109084.9 filed May 29, 2007, which in its entirety areherein incorporated by reference.

BACKGROUND OF THE DISCLOSURE

This invention relates to a novel use of IL-1β-ligand/IL-1 receptordisrupting compounds (herein referred to as “IL-1beta Compounds”); suchas small molecular compounds disrupting IL-1β ligand-IL-1 receptorinteraction, IL-1β antibodies or IL-1 receptor antibodies, e.g. IL-1βbinding molecules described herein, e.g. antibodies disclosed herein,e.g. IL-1β binding compounds or IL-1 receptor binding compounds, and/orRNA compounds decreasing either IL-1β ligands or IL-1 receptor proteinlevels, in the treatment and/or prevention of auto-inflammatorysyndromes, e.g. Juvenile rheumatoid arthritis or adult rheumatoidarthritis syndrome and to methods of treating and/or preventingauto-inflammatory syndromes, e.g. Juvenile rheumatoid arthritis or adultrheumatoid arthritis syndrome, in mammals, particularly humans.

Interleukin-1β (IL-1beta or IL-1β or Interleukin-1β have the samemeaning herein) is a potent immune-modulator which mediates a wide rangeof immune and inflammatory responses. Inappropriate or excessiveproduction of IL-1β is associated with the pathology of various diseasesand disorders, such as septicemia, septic or endotoxic shock, allergies,asthma, bone loss, ischemia, stroke, traumatic brain injury, rheumatoidarthritis and other inflammatory disorders. Antibodies to IL-1β havebeen proposed for use in the treatment of IL-1 mediated diseases anddisorders; see for instance, WO 95/01997 and the discussion in theintroduction thereof and WO 02/16436, the content of which isincorporated by reference.

SUMMARY OF THE DISCLOSURE

In accordance with the present invention, it has now surprisingly beenfound that IL-1beta compounds are useful in the prevention and treatmentof Auto-Inflammatory Syndromes in patients such as in mammals,particularly humans. Auto-Inflammatory Syndromes according to theinventions are e.g., but not limited to, a group of inherited disorderscharacterized by recurrent episodes of inflammation, that in contrast tothe auto-immune diseases lack high-titer autoantibodies or antigenspecific T cells. Furthermore, Auto-inflammatory Syndromes according tothe inventions show increased IL-1beta secretion (loss of negativeregulatory role of pyrin which seems mutated in said diseases), NFkBactivation and impaired leukocyte apoptosis). Auto-inflammatorySyndromes according to the inventions are Muckle-Wells syndromes (MWS),LADA (Latent Autoimmune Diabetes in Adults), familial coldautoinflammmatory syndrome (FCAS), Cryopyrin-associated periodicsyndromes (CAPS), neonatal-onset mutlisystem inflammatory syndrome(NOMID), chronic infantile neurological, cutaneous, articular (CINCA)syndrome, familial Mediterranean fever (FMF) and/or certain form ofjuvenile arthritis such as systemic onset juvenile idiopathic arthritis(SJIA), certain form of juvenile rheumatoid arthritis such as systemiconset juvenile idiopathic rheumatoid arthritis and/or certain form ofadult rheumatoid arthritis. The IL-1beta compounds may also be useful inthe treatment of type 2 diabetes, where clinical and preclinical studiesshow improved islet function by IL-1 blockade. IL-1beta compounds arealso be useful in the treatment of various diabetes related pathologiessuch as retinopathy, wound healing, vascular diseases, (incl. arterialrestenosis after stenting or angioplasty), renal dysfunction, chronickidney disease and metabolic syndrome and obesity. The IL-1betacompounds may also be useful in the treatment of migraine, synovitis,gout, pseudogout/gouty arthritis or chondrocalcinosis, chronicobstructive pulmonary disease (COPD), ventilation induced lung damage,various pain conditions, such as morphine resistant pain, neuropathicpain, pre-term birth pain, discogenic pain, inflammatory pain, headache,or migraine. IL-1beta is involved in pain perception and amplifiesneurogenic signals. Furthermore IL-1beta compounds of the invention areuseful in the treatment of atherosclerosis, actue renal colic, biliarycolic and pain related to these disorders.

The IL-1beta compounds may be useful in the treatment of Periodic FeverSyndromes: Familial Mediterranean Fever (FMF), Tumor Necrosis FactorReceptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin Dsyndrome (HIDS), also called Mevalonate Kinase Associated Periodic FeverSyndrome, Familial Cold auto inflammatory syndrome and Periodic fever,Aphthous-stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome, whereIL-1beta is a dominant cytokine. Other diseases wherein IL-1beta is adominant cytokine and that can be treated with IL-1beta compoundsaccording to the invention comprise Anti-synthetase syndrome, Macrophageactivation syndrome MAS, Behcet Disease, Blau's syndrome, PAPA syndrome,Schnizler's syndrome, Sweet's syndrome. IL-1beta ligand-receptorblocking and IL-1beta compounds of the invention may also be used totreat Vasculitides; Giant-cell arteritis (GCA), Henoch-Schoenleinpurpura, Primary systemic vasculitis, Kawasaki disease (mucocutaneouslymph node syndrome), Takayasu arteritis, Polyarteritis nodosa,Essential cryoglobulinemic vasculitis, microscopic polyangiitis (MPA)and Churg-Strauss syndrome (CSS), urticarial vasculitis. FurthermoreIL-1beta compounds of the invention are useful in the treatment ofautoimmune diseases like sarcoidosis, pemphygus, ankylosing spondylitis,Alzheimer disease, amyloidosis, secondary amyloidosis and adult onsetStill disease (AOSD). IL-1beta compounds of the invention may be used totreat HLA-B27 associated diseases such as but not limited to psoriatica,spondylitis ankylosans, Morbus Reiter and enteropathic arthritis.IL-1beta compounds according to the invention may be used to treatrheumatic fever, polymyalgia rheumatica and giant cell artheriitis.Finally IL-1beta compounds of the invention may be used to treatinfections, in particular bacterial infections and viral infections,more in particular bacterial infections associated with arthriticsymptoms or observations, such as but not limited to hematogenicosteomyelitis, infectious arthritis, tuberculotic arthritis. Preferablythe IL-1beta Compounds are useful in the prevention and treatment ofJuvenile rheumatoid arthritis and adult rheumatoid arthritis and/orMuckle Wells Syndrome.

DETAILED DESCRIPTION OF THE DISCLOSURE

In accordance with the particular findings of the present invention, thefollowing embodiments are provided:

The present invention concerns compositions and methods for theprevention and treatment of Auto-Inflammatory Syndromes in mammals,including humans. Accordingly, the IL-1beta Compounds are also useful toprepare medicines and medicaments for the treatment of Auto-InflammatorySyndromes. In a specific aspect, such medicines and medicaments comprisea therapeutically effective amount of IL-1beta Compounds with apharmaceutically acceptable carrier.

In another embodiment, the invention provides the use of an antibodywhich specifically binds to any of the above or below describedpolypeptides, e.g. IL-1β ligand or IL-1β receptor, preferably IL-1βligand, in the prevention and/or treatment of Juvenile rheumatoidarthritis or adult rheumatoid arthritis syndrome and/or otherAuto-Inflammatory Syndromes and/or Muckle Wells Syndrome. Optionally,the antibody is a monoclonal antibody, humanized antibody, antibodyfragment or single-chain antibody. In one aspect, the present inventionconcerns an isolated antibody which binds a IL-1β ligand. In anotheraspect, the antibody inhibits or neutralizes the activity of a IL-1βligand (an antagonist antibody). In another aspect, the antibody is amonoclonal antibody, which has either a human or nonhumancomplementarily determining region (CDR) residues and human frameworkregion (FR) residues. The antibody may be labeled and may be immobilizedon a solid support. In a further aspect, the antibody is an antibodyfragment, a monoclonal antibody, a single-chain antibody, or ananti-idiotypic antibody. In yet another embodiment, the presentinvention provides a composition comprising an anti-IL-1β ligand orIL-1β receptor antibody, preferably an anti-IL-1β ligand antibody, in amixture with a pharmaceutically acceptable carrier. In one aspect, thecomposition comprises a therapeutically effective amount of theantibody. Preferably, the composition is sterile. The composition may beadministered in the form of a liquid pharmaceutical formulation, whichmay be preserved to achieve extended storage stability. Alternatively,the antibody is a monoclonal antibody, an antibody fragment, a humanizedantibody, or a single-chain antibody.

In another embodiment, the invention provides the use of IL-1betaCompounds, e.g. IL-1beta antibody, which are capable to interrupt thepositive IL-1beta feedback loop in vivo; in the prevention and/ortreatment of Juvenile rheumatoid arthritis or adult rheumatoid arthritisand/or other Auto-Inflammatory Syndromes and/or Muckle Wells Syndrome.This positive feedback in vivo leads to self-sustained overproduction ofIL-1b in these patients.

In another embodiment, the invention provides the use of an IL-1betaCompounds, e.g. IL-1beta antibody, in diseases with a mutation in theMEFV gene, located on chromosome 16p13 and which codes for the proteinpyrin (also known as marenostrin). Pyrin is expressed in granulocytes,monocytes and synovial fibroblasts. Pyrin is involved in IL-1 betaprocessing.

In a further embodiment, the invention concerns an article ofmanufacture, comprising: (a) a composition of matter comprising ananti-IL-1beta ligand or IL-1beta receptor antibody, preferably ananti-IL-1β ligand antibody; (b) a container containing said composition;and (c) a label affixed to said container, or a package insert includedin said container referring to the use of said anti-IL-1 ligand or IL-1βreceptor antibody, preferably an anti-IL-1 ligand antibody, in thetreatment of Juvenile rheumatoid arthritis or adult rheumatoid arthritisand/or other Auto-Inflammatory Syndromes and/or Muckle Wells Syndrome.The composition may comprise a therapeutically effective amount of ananti-IL-1β ligand or IL-1β receptor antibody, preferably an anti-IL-1βligand.

In yet a further embodiment, the invention provides a method or use asdefined above, comprising co-administration of a therapeuticallyeffective amount of IL-1beta Compounds in free form or salt form,preferably in a pharmaceutically acceptable delivery form such asintravenously or subcutaneously, and a second drug substance, saidsecond drug substance being an Anti-inflammatory Compound in free formor salt form.

In yet a further embodiment, an IL-1beta Compounds used according to theinvention is an IL-1β binding molecule which comprise an antigen bindingsite comprising at least one immunoglobulin heavy chain variable domain(V_(H)) which comprises in sequence hypervariable regions CDR1, CDR2 andCDR3, said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn (SEQID NO:3), said CDR2 having the amino acid sequenceIle-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQID NO:4), and said CDR3 having the amino acid sequenceAsp-Leu-Arg-Thr-Gly-Pro (SEQ ID NO:5); and direct equivalents thereof.

In yet a further embodiment, an IL-1beta Compound used according to theinvention is an IL-1β binding molecule which comprise at least oneimmunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ havingthe amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His (SEQID NO:6) said CDR2′ having the amino acid sequenceAla-Ser-Gln-Ser-Phe-Ser (SEQ ID NO:7) and said CDR3′ having the aminoacid sequence His-Gln-Ser-Ser-Ser-Leu-Pro (SEQ ID NO:8) and directequivalent thereof.

In yet a further embodiment, an IL-1beta Compound used according to theinvention is a single domain IL-1beta binding molecule comprising anisolated immunoglobulin heavy chain comprising a heavy chain variabledomain (V_(H)) as defined above, e.g. for the preparation of amedicament for the treatment of Juvenile rheumatoid arthritis or adultrheumatoid arthritis syndrome and/or other Autoinflammatory Syndromes,preferably Juvenile rheumatoid arthritis or adult rheumatoid arthritissyndrome and/or Muckle Wells Syndrome.

In yet a further embodiment, an IL-1beta Compound used according to theinvention is an IL-1β binding molecule comprising both heavy (V_(H)) andlight chain (V_(L)) variable domains in which said IL-1β bindingmolecule comprises at least one antigen binding site comprising:

-   -   a) an immunoglobulin heavy chain variable domain (V_(H)) which        comprises in sequence hypervariable regions CDR1, CDR2 and CDR3,        said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn        (SEQ ID NO:3), said CDR2 having the amino acid sequence        Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly        (SEQ ID NO:4), and said CDR3 having the amino acid sequence        Asp-Leu-Arg-Thr-Gly-Pro (SEQ ID NO:5), and    -   b) an immunoglobulin light chain variable domain (V_(L)) which        comprises in sequence hypervariable regions CDR1′, CDR2′ and        CDR3′, said CDR1′ having the amino acid sequence        Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His (SEQ ID NO:6), said        CDR2′ having the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser        (SEQ ID NO:7), and said CDR3′ having the amino acid sequence        His-Gln-Ser-Ser-Ser-Leu-Pro (SEQ ID NO:8);        and direct equivalents thereof.

Unless otherwise indicated, any polypeptide chain is herein described ashaving an amino acid sequence starting at the N-terminal extremity andending at the C-terminal extremity. When the antigen binding sitecomprises both the V_(H) and V_(L) domains, these may be located on thesame polypeptide molecule or, preferably, each domain may be on adifferent chain, the V_(H) domain being part of an immunoglobulin heavychain or fragment thereof and the V_(L) being part of an immunoglobulinlight chain or fragment thereof.

By “IL-1β binding molecule” is meant any molecule capable of binding tothe IL-1β ligand either alone or associated with other molecules. Thebinding, reaction may be shown by standard methods (qualitative assays)including, for example, a bioassay for determining the inhibition ofIL-1β binding to its receptor or any kind of binding assays, withreference to a negative control test in which an antibody of unrelatedspecificity but of the same isotype, e.g. an anti-CD25 antibody, isused. Advantageously, the binding of the IL-1β binding molecules of theinvention to IL-1β may be shown in a competitive binding assay.

Examples of antigen binding molecules include antibodies as produced byB-cells or hybridomas and chimeric, CDR-grafted or human antibodies orany fragment thereof, e.g. F(ab′)₂ and Fab fragments, as well as singlechain or single domain antibodies.

A single chain antibody consists of the variable domains of the heavyand light chains of an antibody covalently bound by a peptide linkerusually consisting of from 10 to 30 amino acids, preferably from 15 to25 amino acids. Therefore, such a structure does not include theconstant part of the heavy and light chains and it is believed that thesmall peptide spacer should be less antigenic than a whole constantpart. By “chimeric antibody” is meant an antibody in which the constantregions of heavy or light chains or both are of human origin while thevariable domains of both heavy and light chains are of non-human (e.g.murine) origin or of human origin but derived from a different humanantibody. By “CDR-grafted antibody” is meant an antibody in which thehypervariable regions (CDRs) are derived from a donor antibody, such asa non-human (e.g. murine) antibody or a different human antibody, whileall or substantially all the other parts of the immunoglobulin e.g. theconstant regions and the highly conserved parts of the variable domains,i.e. the framework regions, are derived from an acceptor antibody, e.g.an antibody of human origin. A CDR-grafted antibody may however containa few amino acids of the donor sequence in the framework regions, forinstance in the parts of the framework regions adjacent to thehypervariable regions. By “human antibody” is meant an antibody in whichthe constant and variable regions of both the heavy and light chains areall of human origin, or substantially identical to sequences of humanorigin, not necessarily from the same antibody and includes antibodiesproduced by mice in which the murine immunoglobulin variable andconstant part genes have been replaced by their human counterparts, e.g.as described in general terms in EP 0546073 B1, U.S. Pat. No. 5,545,806,U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No.5,633,425, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,770,429, EP 0438-474 B1 and EP 0 463151 B1.

The phrase direct equivalents encompasses any molecule, antibody orfunctional fragment thereof having the properties of an IL-1beta bindingmolecule of the invention as provided in this description, includingantibodies of various species and isotypes, Fab2, Fab and scFv fragmentsand mutants comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pointmutations in the CDR regions or outside the CDR regions of SEQ ID NO:1and 2.

Particularly preferred IL-1β binding molecules of the invention arehuman antibodies especially the ACZ 885 antibody as hereinafterdescribed in the Examples and in WO 02/16436.

Thus in preferred antibodies of the invention, the variable domains ofboth heavy and light chains are of human origin, for instance those ofthe ACZ 885 antibody which are shown in SEQ ID NO:1 and SEQ ID NO:2. Theconstant region domains preferably also comprise suitable human constantregion domains, for instance as described in “Sequences of Proteins ofImmunological Interest”, Kabat E. A. et al, US Department of Health andHuman Services, Public Health Service, National Institute of Health.

Hypervariable regions may be associated with any kind of frameworkregions, though preferably are of human origin. Suitable frameworkregions are described in Kabat E. A. et al, ibid. The preferred heavychain framework is a human heavy chain framework, for instance that ofthe ACZ 885 antibody which is shown in SEQ ID NO:1. It consists insequence of FR1, FR2, FR3 and FR4 regions. In a similar manner, SEQ IDNO:2 shows the preferred ACZ 885 light chain framework which consists,in sequence, of FR1′, FR2′, FR3′ and FR4′ regions.

Accordingly, the invention also provides an IL-1β binding molecule whichcomprises at least one antigen binding site comprising either a firstdomain having an amino acid sequence substantially identical to thatshown in SEQ ID NO:1 starting with the amino acid at position 1 andending with the amino acid at position 118 or a first domain asdescribed above and a second domain having an amino acid sequencesubstantially identical to that shown in SEQ ID NO:2, starting with theamino acid at position 1 and ending with the amino acid at position 107.

Monoclonal antibodies raised against a protein naturally found in allhumans are typically developed in a non-human system e.g. in mice, andas such are typically non-human proteins. As a direct consequence ofthis, a xenogenic antibody as produced by a hybridoma, when administeredto humans, elicits an undesirable immune response which is predominantlymediated by the constant part of the xenogenic immunoglobulin. Thisclearly limits the use of such antibodies as they cannot be administeredover a prolonged period of time. Therefore it is particularly preferredto use single chain, single domain, chimeric, CDR-grafted, or especiallyhuman antibodies which are not likely to elicit a substantial allogenicresponse when administered to humans.

In view of the foregoing, a more preferred IL-1β binding molecule of theinvention is selected from a human anti IL-1β antibody which comprisesat least

-   -   a) an immunoglobulin heavy chain or fragment thereof which        comprises (i) a variable domain comprising in sequence the        hypervariable regions CDR1, CDR2 and CDR3 and (ii) the constant        part or fragment thereof of a human heavy chain; said CDR1        having the amino acid sequence Val-Tyr-Gly-Met-Asn (SEQ ID        NO:3), said CDR2 having the amino acid sequence        Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly        (SEQ ID NO:4), and said CDR3 having the amino acid sequence        Asp-Leu-Arg-Thr-Gly-Pro (SEQ ID NO:5) and    -   b) an immunoglobulin light chain or fragment thereof which        comprises (i) a variable domain comprising in sequence the        hypervariable regions and optionally also the CDR1′, CDR2′, and        CDR3′ hypervariable regions and (ii) the constant part or        fragment thereof of a human light chain, said CDR1′ having the        amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His        (SEQ ID NO:6), said CDR2′ having the amino acid sequence        Ala-Ser-Gln-Ser-Phe-Ser (SEQ ID NO:7), and said CDR3′ having the        amino acid sequence His-Gln-Ser-Ser-Ser-Leu-Pro (SEQ ID NO:8);        and direct equivalents thereof.

Alternatively, an IL-1β binding molecule of the invention may beselected from a single chain binding molecule which comprises an antigenbinding site comprising

-   a) a first domain comprising in sequence the hypervariable regions    CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence    Val-Tyr-Gly-Met-Asn (SEQ ID NO:3), said CDR2 having the amino acid    sequence    Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly    (SEQ ID NO:4), and said CDR3 having the amino acid sequence    Asp-Leu-Arg-Thr-Gly-Pro (SEQ ID NO:5),-   b) A second domain comprising the hypervariable regions CDR1′, CDR2′    and CDR3′, said CDR1′ having the amino acid sequence    Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His (SEQ ID NO:6), said    CDR2′ having the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser (SEQ ID    NO:7), and said CDR3′ having the amino acid sequence    His-Gln-Ser-Ser-Ser-Leu-Pro (SEQ ID NO:8) and-   c) a peptide linker which is bound either to the N-terminal    extremity of the first domain and to the C-terminal extremity of the    second domain or to the C-terminal extremity of the first domain and    to the N-terminal extremity of second domain;    and direct equivalents thereof.

As it is well known, minor changes in an amino acid sequence such asdeletion, addition or substitution of one, a few or even several aminoacids may lead to an allelic form of the original protein which hassubstantially identical properties.

Thus, by the term “direct equivalents thereof” is meant either anysingle domain IL-1β binding molecule (molecule X)

-   (i) in which the hypervariable regions CDR1, CDR2 and CDR3 taken as    a whole are at least 80% homologous, preferably at least 90%    homologous, more preferably at least 95% homologous to the    hypervariable regions as shown above and,-   (ii) which is capable of inhibiting the binding of IL-1β to its    receptor substantially to the same extent as a reference molecule    having framework regions identical to those of molecule X but having    hypervariable regions CDR1, CDR2 and CDR3 identical to those shown    in above,    or any IL-1β binding molecule having at least two domains per    binding site (molecule X′)-   (i) in which the hypervariable regions CDR1, CDR2, CDR3, CDR1′,    CDR2′ and CDR3′ taken as a whole are at least 80% homologous,    preferably at least 90% homologous, more preferably at least 95, 98    or 99% homologous, to the hypervariable regions as shown above and-   (ii) which is capable of inhibiting the binding of IL-1β to its    receptor substantially to the same extent as a reference molecule    having framework regions and constant parts identical to molecule    X′, but having hypervariable regions CDR1, CDR2, CDR3, CDR1′, CDR2′    and CDR3′, identical to those shown above.

In a further aspect the invention also provides an IL-1beta bindingmolecule comprising both heavy (V_(H)) and light chain (V_(L)) variabledomains in which said IL-1beta binding molecule comprises at least oneantigen binding site comprising:

-   -   a) an immunoglobulin heavy chain variable domain (V_(H)) which        comprises in sequence hypervariable regions CDR1, CDR2 and CDR3,        said CDR1 having the amino acid sequence Ser-Tyr-Trp-Ile-Gly        (SEQ ID NO:9), said CDR2 having the amino acid sequence        Ile-Ile-Tyr-Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly        (SEQ ID NO:4), and said CDR3 having the amino acid sequence        Tyr-Thr-Asn-Trp-Asp-Ala-Phe-Asp-Ile (SEQ ID NO:10), and    -   b) an immunoglobulin light chain variable domain (V_(L)) which        comprises a CDR3′ hypervariable region having the amino acid        sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-Phe-Pro (SEQ ID NO:11);        and direct equivalents thereof.

In further aspect the invention provides an IL-1beta binding moleculecomprising both heavy (V_(H)) and light (V_(L)) chain variable domainsin which said IL-1beta binding molecule comprises at least one antigenbinding site comprising:

-   -   a) an immunoglobulin heavy chain variable domain (V_(H)) which        comprises in sequence hypervariable regions CDR1, CDR2 and CDR3,        said CDR1 having the amino acid sequence Ser-Tyr-Trp-Ile-Gly        (SEQ ID NO:9), said CDR2 having the amino acid sequence        Ile-Ile-Tyr-Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly        (SEQ ID NO:4), and said CDR3 having the amino acid sequence        Tyr-Thr-Asn-Trp-Asp-Ala-Phe-Asp-Ile (SEQ ID NO:10), and    -   b) an immunoglobulin light chain variable domain (V_(L)) which        comprises in sequence hypervariable regions CDR1′, CDR2′ and        CDR3′, said CDR1′ having the amino acid sequence        Arg-Ala-Ser-Gln-Ser-Val-Ser-Ser-Tyr-Leu Ala (SEQ ID NO:6), said        CDR2′ having the amino acid sequence Asp-Ala-Ser-Asn-Arg-Ala-Thr        (SEQ ID NO:12), and said CDR3′ having the amino acid sequence        Gln-Gln-Arg-Ser-Asn-Trp-Met-Phe-Pro (SEQ ID NO:11);        and direct equivalents thereof.

In the present description amino acid sequences are at least 80%homologous to one another if they have at least 80% identical amino acidresidues in a like position when the sequence are aligned optimally,gaps or insertions in the amino acid sequences being counted asnon-identical residues.

The inhibition of the binding of IL-1β to its receptor may beconveniently tested in various assays including such assays aredescribed in WO 02/16436. By the term “to the same extent” is meant thatthe reference and the equivalent molecules exhibit, on a statisticalbasis, essentially identical IL-1β binding inhibition curves in one ofthe assays referred to above. For example, in IL-1β binding molecules ofthe invention typically have IC₅₀s for the inhibition of the binding ofIL-1β to its receptor which are within +/−×5 of that of, preferablysubstantially the same as, the IC₅₀ of the corresponding referencemolecule when assayed as described above.

For example, the assay used may be an assay of competitive inhibition ofbinding of IL-1β by soluble IL-1 receptors and the IL-1β bindingmolecules of the invention.

Most preferably, the IL-1β binding molecule for use according to theinvention is an human IL-1 antibody which comprises at least

-   -   a) one heavy chain which comprises a variable domain having an        amino acid sequence substantially identical to that shown in SEQ        ID NO:1 starting with the amino acid at position 1 and ending        with the amino acid at position 118 and the constant part of a        human heavy chain; and    -   b) one light chain which comprises a variable domain having an        amino acid sequence substantially identical to that shown in SEQ        ID NO:2 starting with the amino acid at position 1 and ending        with the amino acid at position 107 and the constant part of a        human light chain.

Most preferably, the IL-1β binding molecule for use according to theinvention is ACZ885 (see Example).

The constant part of a human heavy chain may be of the γ₁, γ₂, γ₃, γ₄,μ, α₁, α₂, δ or ε type, preferably of the γ type, more preferably of theγ₁ type, whereas the constant part of a human light chain may be of theκ or λ type (which includes the λ₁, λ₂ and λ₃ subtypes) but ispreferably of the κ type. The amino acid sequences of all these constantparts are given in Kabat et al ibid.

An IL-1β binding molecule of the invention may be produced byrecombinant DNA techniques as e.g. described in WO 02/16436.

In yet another embodiment of the invention, IL-1beta Compounds may beantibodies which have binding specificity for the antigenic epitope ofhuman IL-1β which includes the loop comprising the Glu 64 residue ofmature human IL-1β (Residue Glu 64 of mature human IL-1β correspond toresidue 180 of the human IL-1beta precursor). This epitope is outsidethe recognition site of the IL-1beta receptor and it is therefore mostsurprising that antibodies to this epitope, e.g. the ACZ 885 antibody,are capable of inhibiting the binding of IL-1β to its receptor. Thus theuse of such antibodies for the treatment of Juvenile rheumatoidarthritis and adult rheumatoid arthritis and/or Auto-InflammatorySyndromes and/or Muckle Wells Syndrome is novel and are included withinthe scope of the present invention.

Thus in a further aspect the invention includes the use of an antibodyto IL-1β which has antigen binding specificity for an antigenic epitopeof human IL-1β which includes the loop comprising residue Glu 64 ofmature human IL-1β and which is capable of inhibiting the binding ofIL-1β to its receptor for the treatment of Juvenile rheumatoid arthritisor adult rheumatoid arthritis and/or Auto-Inflammatory Syndromes and/orMuckle Wells Syndrome.

In yet further aspects the invention includes:

-   -   i) use of an antibody to IL-1β, which has antigen binding        specificity for an antigenic epitope of mature human IL-1β which        includes the loop comprising Glu 64 and which is capable of        inhibiting the binding of IL-1β to its receptor, for the        prevention and/or treatment of Juvenile rheumatoid arthritis or        adult rheumatoid arthritis and/or Auto-Inflammatory Syndromes        and/or Muckle Wells Syndrome,    -   ii) a method for the prevention and/or treatment of Juvenile        rheumatoid arthritis or adult rheumatoid arthritis and/or        Auto-Inflammatory Syndromes and/or Muckle Wells Syndrome in a        patient which comprises administering to the patient an        effective amount of an antibody to IL-1β which has antigen        binding specificity for an antigenic epitope of mature human        IL-1β which includes the loop comprising Glu 64 and which is        capable of inhibiting the binding of IL-1β to its receptor;    -   iii) a pharmaceutical composition comprising an antibody to        IL-1β, which has antigen binding specificity for an antigenic        epitope of mature human IL-1β which includes the loop comprising        Glu 64 and which is capable of inhibiting the binding of IL-1β        to its receptor, in combination with a pharmaceutically        acceptable excipient, diluent or carrier; for the treatment of        Juvenile rheumatoid arthritis or adult rheumatoid arthritis        syndrome and/or Auto-Inflammatory Syndromes and/or Muckle Wells        Syndrome.    -   iv) use of an antibody to IL-1β, which has antigen binding        specificity for an antigenic epitope of mature human IL-1β which        includes the loop comprising Glu 64 and which is capable of        inhibiting the binding of IL-1β to its receptor, for the        preparation of a medicament for the treatment of Juvenile        rheumatoid arthritis or adult rheumatoid arthritis syndrome        and/or Auto-Inflammatory Syndromes and/or Muckle Wells Syndrome.

For the purposes of the present description an antibody is “capable ofinhibiting the binding of IL-1β ” if the antibody is capable ofinhibiting the binding of IL-1β to its receptor substantially to thesame extent as the ACZ 885 antibody, i.e. has a dissociation equilibriumconstant (K_(D)) measured e.g. in a standard BIAcore analysis asdisclosed in the Example of 10 nM or lower, e.g. 1 nM or lower,preferably 100 μM or lower, more preferably 50 μM or lower.

Thus in a yet further aspect the invention provides the use of anantibody to IL-1β which has a K_(D) for binding to IL-1β of about 10 nM,1 nM, preferably 100 μM, more preferably 50 μM or less for the treatmentof Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndromeand/or Auto-Inflammatory Syndromes. This aspect of the invention alsoincludes uses methods and compositions for such high affinityantibodies, as described above for antibodies to IL-1β have bindingspecificity for an antigenic determinant of mature human IL-1β whichincludes the loop comprising Glu 64.

In the present description the phrase “Juvenile rheumatoid arthritis oradult rheumatoid arthritis syndrome and/or Auto-Inflammatory Syndromes”encompasses all diseases and medical conditions which are part ofJuvenile rheumatoid arthritis or adult rheumatoid arthritis syndromeand/or Auto-Inflammatory Syndromes, whether directly or indirectly, inthe disease or medical condition, including the causation, development,progress, persistence or pathology of the disease or condition.

In the present description the phrase “Muckle Wells Syndrome” (also“MWS”) encompasses all diseases and medical conditions which are part of“Muckle Wells Syndrome”, whether directly or indirectly, in the diseaseor medical condition, including the causation, development, progress,persistence or pathology of the disease or condition.

The compounds of formula I may be administered as the sole activeingredient or in conjunction with, e.g. as an adjuvant to, other drugse.g. immunosuppressive or immunomodulating agents or otheranti-inflammatory agents, e.g. for the treatment or prevention of allo-or xenograft acute or chronic rejection or inflammatory or autoimmunedisorders, or a chemotherapeutic agent, e.g a malignant cellanti-proliferative agent. For example, the antibodies according to theinvention may be used in combination with a calcineurin inhibitor, e.g.cyclosporin A or FK 506; a mTOR inhibitor, e.g. rapamycin,40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464,AP23675, AP23841, TAFA-93, biolimus-7 or biolimus-9; an ascomycin havingimmunosuppressive properties, e.g. ABT-281, ASM981, etc.;corticosteroids; cyclo-phosphamide; azathioprene; methotrexate;leflunomide; mizoribine; mycophenolic acid or salt; mycophenolatemofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogueor derivative thereof; a PKC inhibitor, e.g. as disclosed in WO 02/38561or WO 03/82859, e.g. the compound of Example 56 or 70; a JAK3 kinaseinhibitor, e.g. N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide

-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490),prodigiosin 25-C (PNU156804),[4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131),[4-(3′-bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline](WHI-P154),[4-(3′,5′-dibromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline]WHI-P97, KRX-211,3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile,in free form or in a pharmaceutically acceptable salt form, e.g.mono-citrate (also called CP-690,550), or a compound as disclosed in WO04/052359 or WO 05/066156; immunosuppressive monoclonal antibodies,e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3,CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or theirligands; other immunomodulatory compounds, e.g. a recombinant bindingmolecule having at least a portion of the extracellular domain of CTLA4or a mutant thereof, e.g. an at least extracellular portion of CTLA4 ora mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4Ig(for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y;adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3antagonists, VCAM-4 antagonists or VLA-4 antagonists; or achemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum,doxorubicin or 5-fluorouracil; or an anti-infectious agent.Immunomodulatory drugs which are prone to be useful in combination witha compound of the present invention include e.g.

-   -   mediators, e.g. inhibitors, of mTOR activity, including        rapamycin of formula

-   -   and rapamycin derivatives, e.g. including    -   40-O-alkyl-rapamycin derivatives, such as        40-O-hydroxyalkyl-rapamycin derivatives, such as        40-O-(2-hydroxy)-ethyl-rapamycin (everolimus),    -   32-deoxo-rapamycin derivatives and 32-hydroxy-rapamycin        derivatives, such as 32-deoxorapamycin,    -   16-O-substituted rapamycin derivatives such as        16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or        R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or        R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin,    -   rapamycin derivatives which are acylated at the oxygen group in        position 40, e.g.        40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin        (also known as CCI779), rapamycin derivatives which are        substituted in 40 position by heterocyclyl, e.g.        40-epi-(tetrazolyl)-rapamycin (also known as ABT578),    -   the so-called rapalogs, e.g. as disclosed in WO9802441,        WO0114387 and WO0364383, such as AP23573, and    -   compounds disclosed under the name TAFA-93 and biolimus        (biolimus A9).

The IL-1beta compounds according to the invention may be administered asthe sole active ingredient or in conjunction with bisphosphonates,sequential, simultaneous or combined in one formulation. Bisphosphonatesto be used in conjunction with the IL-1beta molecules of the inventioncomprise etidronate, clodronate, tiludronate, pamidronate, neridronate,olpadronate, alendronate, ibandronate, risedronate, zoledronate, and anysalt, acid, polymorph or derivative thereof.

IL-1beta compounds on the invention may advantageously be combined withProtein Kinase C Inhibitors and/or suppressors of T cell activation, inparticular indolylmaleimide derivatives such as sotrastaurin(3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione),for instance in order to inhibit the adaptive immune system and therebyfurther enhancing the therapeutic effects of IL-1beta compounds.

IL-1beta compounds of the invention may also advantageously be combinedwith anti-cytokines and/or anti-interleukins, in particular IL-17binding compounds disclosed in WO2006/013107, optionally in combinationwith sotrastaurin.

IL-1beta compounds of the invention may advantageously be combined withanti TNFalpha compounds such as etanercept, adalimumab, infliximab, forinstance in the treatment of RA and other (auto)-inflammatory diseases.

In the present description the terms “treatment” or “treat” refer toboth prophylactic or preventative treatment as well as curative ordisease modifying treatment, including treatment of patient at risk ofcontracting the disease or suspected to have contracted the disease aswell as patients who are ill or have been diagnosed as suffering from adisease or medical condition, and includes suppression of clinicalrelapse. A successful treatment according to the invention also includesremissions of all reparable symptoms but no remissions of irreparablesymptoms. E.g. one of the symptoms of Mucke-Wells is the progressivenerve deafness which is normally irreparable and thus there is noexpectation that this symptom may be treated. However, other reparablesymptoms of Muckle-Wells such as skin rash, muscle pain fever, fatigueand conjunctivitis may be completely disappear in a successful treatmentaccording to the invention. Another measure of a successful treatment isthe decrease of relevant biomarkers for Auto-Inflammatory Syndromes,e.g. Muckle-Wells, i.e. the decrease of serum amyloid protein (SAA) andc-reactive protein (CRP) to normal range, i.e. <10 mg per L serum inpatients.

In the present description, the disease “Muckle-Wells” is among others(molecular pathology) determined according to its clinical symptomswhich are acute febrile inflammatory episodes of arthritis andurticaria, progressive nerve deafness and optionally long term multiorgan amyloidosis (about 25% of cases). Molecular pathology is caused byone or several mutations in the MEFV gene, located on chromosome 16p13,which codes for the protein named pyrin.

IL-1β binding molecules as defined above, in particular IL-1β bindingmolecules according to the first and second aspects of the inventionantibodies which have binding specificity for the antigenic epitope ofmature human IL-1β which includes the loop comprising Glu 64, inparticular antibodies which are capable of inhibiting the binding ofIL-1β to its receptor; and antibodies to IL-16 which have a K_(D) forbinding to IL-16 of about 10 nM, 1 nM, preferably 100 pM, morepreferably 50 pM or less are herein referred to as Antibodies of theInvention.

In yet another embodiment of the invention, the further uses of theIL-1beta Compounds, e.g. the Antibodies of the Invention are as follows:

Prevention and treatment of Inflammatory Bowl Disease (IBD), Juvenilearthritis, reactive arthritis, ankylsoing spondylitis, coronarysyndrome, arterial restenosis, cystic fibrosis, Alzheimer's disease,multiple myeloma, arteriosclerosis, pulmonary fibrosis, Muckle-Wells andChronic Obstructive Pulmonary Disease (COPD).

For all indications disclosed herein this description (Indications ofthe inventions), the appropriate dosage will, of course, vary dependingupon, for example, the particular IL-1beta Compounds, e.g. the Antibodyof the Invention to be employed, the host, the mode of administrationand the nature and severity of the condition being treated. However, inprophylactic use, satisfactory results are generally indicated to beobtained at dosages from about 0.05 mg to about 10 mg per kilogram bodyweight more usually from about 0.1 mg to about 5 mg per kilogram bodyweight. Antibody of the Invention is conveniently administeredparenterally, intravenously, e.g. into the antecubital or otherperipheral vein, intramuscularly, or subcutaneously.

In yet another embodiment, the invention concerns a surprising frequencyof dosing for therapeutic uses, i.e. the treatment schedule withIL-1beta Compounds, preferably IL-1beta antibodies, more preferablyACZ885 (at a typical dose, e.g. between about 0.1 mg to about 50 mg,more preferably between 0.5 mg to 20 mg, even more preferably from 1 mgto 10 mg, of ACZ885 per kg body weight of the patient) may be once everyweek or less frequently, more preferably once every 2 weeks or lessfrequently, more preferably once every 3 weeks or less frequently, morepreferably once every month or less frequently, more preferably onceevery 2 months or less frequently, more preferably once every 3 monthsor less frequently, even more preferably once every 4 months or lessfrequently, even more preferably once every 5 months or less frequently,or even more preferably once every 6 months or less frequently. Mostpreferred is once every month.

Pharmaceutical compositions of the invention may be manufactured inconventional manner. A composition according to the invention ispreferably provided in lyophilized form. For immediate administration itis dissolved in a suitable aqueous carrier, for example sterile waterfor injection or sterile buffered physiological saline. If it isconsidered desirable to make up a solution of larger volume foradministration by infusion rather as a bolus injection, it isadvantageous to incorporate human serum albumin or the patient's ownheparinised blood into the saline at the time of formulation. Thepresence of an excess of such physiologically inert protein preventsloss of antibody by adsorption onto the walls of the container andtubing used with the infusion solution. If albumin is used, a suitableconcentration is from 0.5 to 4.5% by weight of the saline solution.

The invention is further described by way of illustration in thefollowing Examples.

EXAMPLES Example 1 ACZ885

Structure and making of ACZ885 are e.g. described in WO 02/16436. Inshort, the amino-terminal sequences of heavy and light chain variabledomains and the corresponding DNA sequences are given in SEQ ID NO:1 andSEQ ID NO:2.

Example 2 Biochemical and Biological Data of ACZ885

The monoclonal antibody ACZ 885 is found to neutralize the activity ofinterleukin-1β in vitro. The monoclonal antibody is furthercharacterized for its binding to recombinant human IL-1β by surfaceplasmon resonance analysis. The mode of neutralization is assessed bycompetitive binding studies with soluble IL-1 receptors. The biologicalactivity of the antibody ACZ 885 towards recombinant and naturallyproduced IL-1β is determined in primary human cell, responsive tostimulation by IL-1β.

Determination of Dissociation Equilibrium Constant

The association and dissociation rate constants for the binding ofrecombinant human IL-1beta to ACZ885 are determined by surface plasmonresonance analysis. ACZ885 is immobilized, and binding of recombinantIL-1beta in a concentration range from 1 to 4 nM is measured by surfaceplasmon resonance. The chosen format represents a monovalent interactionand thus permits treating the binding event of IL-1beta to ACZ885according to a 1:1 stoichiometry. Data analysis is performed using theBIAevaluation software.

k_(on) k_(off) K_(D) [10⁵/Ms] [10⁻⁵/s] [pM] ACZ885 11.0 +/− 0.23 3.3 +/−0.27 30.5 +/− 2.6 n = 22 Conclusion: ACZ885 binds to recombinant humanIL-1beta with very high affinity.

Example 3 Clinical Trial with ACZ885

In order to asses the suitability of an IL-1beta Compound, e.g. ACZ885,an open-label, single center dose titration study of ACZ885 (humananti-IL-1 beta monoclonal antibody) to assess the clinical efficacy,safety, pharmacokinetics and pharmacodynamics in patients with MWsyndrome, characterized by NALP3 mutations, is conducted.

Patients are treated by a single dose infusion of ACZ885 (10 mg/kgi.v.). Clinical response is measured by improvement of symptoms (e.g.,skin rash, muscle pain, fever, fatigue) and by lowering of acute phaseproteins serum amyloid protein (SAA) and c-reactive protein (CRP). Inaddition, response to treatment is assessed by the analysis of mRNAobtained from peripheral blood cells. A second treatment (1 mg/kg i.v.)is given after re-appearance of clinical symptoms. Results: Clinicalremission of symptoms (fever, rash, conjunctivitis) within 3 days, anddecrease of CRP and SM to normal range (<10 mg/L) in patients. Clinicalremission of symptoms with first infusion lasts for at least 134 days,typically between 160 and 200 days. Upon second treatment with lowerdose, patients respond with improvement of symptoms and normalization ofacute phase proteins.

Analysis of mRNA obtained from peripheral blood cells demonstratesdownregulation of the transcription of IL-1b and IL-1b-induced geneswithin 24 h upon treatment with ACZ885. This suggests that ACZ885 iscapable to interrupt a positive feedback loop in vivo which leads toself-sustained overproduction of IL-1b in these patients. Thiscontention is also supported by initial characterization of PK/PDeffects of ACZ885 which demonstrates the blockade of production of IL-1bupon treatment with ACZ885 in these patients. This particular ability ofACZ885 may contribute (be causal) for its long-lasting clinical effect.

1.-3. (canceled)
 4. A method of treating an auto-inflammatory syndromein a patient in need thereof, comprising administering to said patientan effective amount of an IL-1beta binding molecule comprising anantigen binding site comprising at least one immunoglobulin heavy chainvariable domain (V_(H)) which comprises in sequence hypervariableregions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequenceVal-Tyr-Gly-Met-Asn, said CDR2 having the amino acid sequenceIle-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly, andsaid CDR3 having the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro; anddirect equivalents thereof.
 5. A method of treating an auto-inflammatorysyndrome in a patient in need thereof, comprising administering to saidpatient an effective amount of an IL-1beta binding molecule comprisingboth heavy (V_(H)) and light chain (V_(L)) variable domains in whichsaid IL-1beta binding molecule comprises at least one antigen bindingsite comprising: a) an immunoglobulin heavy chain variable domain(V_(H)) which comprises in sequence hypervariable regions CDR1, CDR2 andCDR3, said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn, saidCDR2 having the amino acid sequenceIle-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly, andsaid CDR3 having the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro, and b)an immunoglobulin light chain variable domain (V_(I)) which comprises insequence hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ havingthe amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His,said CDR2′ having the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser, andsaid CDR3′ having the amino acid sequence His-Gln-Ser-Ser-Ser-Leu-Pro;and direct equivalents thereof.
 6. The, method according to claim 5,wherein the IL-1beta binding molecule comprises a first domain having anamino acid sequence substantially identical to that shown in SEQ ID NO:1and a second domain having an amino acid sequence substantiallyidentical to that shown in SEQ ID NO:2.
 7. The method according to claim6, wherein the auto-inflammatory syndrome is Juvenile rheumatoidarthritis or adult rheumatoid arthritis syndrome or Muckle WellsSyndrome.
 8. The method according to claim 7 wherein the IL-beta bindingmolecule is applied once every week or less frequently.
 9. The methodaccording to claim 8, wherein the IL-beta binding molecule is appliedsubcutaneously.